Although no formal definition exists for what constitutes a rapidly progressive dementia (RPD), generally we use the term when dementia occurs in <1–2 years from illness onset, but more commonly over weeks to months. Prion diseases are the prototypical causes of RPD, but reversible causes of RPD might mimic prion disease and should always be considered in a differential diagnosis. We report the case of a 65-year-old male with progressive dementia and typical neurologic symptoms, myoclonic jerks, and magnetic resonance imaging findings of Creutzfeldt–Jakob disease (CJD). This case highlights the need for a high index of suspicion to diagnose CJD.

Although no formal definition exists for what constitutes a rapidly progressive dementia (RPD), generally we use the term when dementia occurs in <1–2 years from illness onset, but more commonly over weeks to months.[1] Because these conditions are relatively uncommon, the appropriate diagnostic workup and treatments often are unfamiliar to many neurologists. Accurate, thorough, and prompt diagnosis is important as many RPDs are treatable and even curable. The subacute nature of RPD excludes other conditions with fulminant progression such as infectious or metabolic acute encephalopathies, which progress within hours or days and typically commence as an acute confusional state. In most cases, the cognitive decline observed in RPD can be attributed to a single underlying disorder. Nevertheless, a rapid course might also represent the aggravation of an undiagnosed disease attributable to a secondary cause, usually an infection or a metabolic dysregulation.[2] Various conditions involving the central nervous system can emerge as RPD including Creutzfeldt–Jakob disease (CJD) and other spongiform encephalopathies, vascular disorders, autoimmune and paraneoplastic encephalopathies, subacute infections, metabolic and toxic disorders, and systemic diseases.[2]

Prion diseases

Prion diseases are the prototypical causes of RPD, but reversible causes of RPD might mimic prion disease and should always be considered in a differential diagnosis. Prion diseases are a group of neurodegenerative diseases caused by the conversion of the normal prion protein (PrPC, prion-related protein, in which C stands for the cellular form of the protein) with a primarily helical structure into an abnormal form of the protein called the prion (PrPSc, in which Sc stands for scrapie - the prion disease of sheep and goats). Prion is proteinaceous infectious particle that has a primarily β-pleated sheet structure. Alfons Jakob described the first cases of human prion disease between 1921 and 1923 and thought his cases were similar to a young woman described by Creutzfeldt in 1920.[3],[4]

Creutzfeldt–Jakob disease

CJD is the most common human prion disease and falls into four categories: sporadic (85%), familial (10%–15%), iatrogenic (1%), and variant.[1] CJD is an illness typically involving progressive dementia with a fatal and incurable course.[5] CJD is a rare, fatal neurodegenerative disease caused by an infectious protein called prion and is characterized by spongiform changes, neuronal loss, reactive astrocytic proliferation, and accumulation of pathologic cellular protein. Clinical presentation of CJD is characterized by RPD, neurologic symptoms and visual impairment, and the development of akinetic mutism, which can mimic many neurological conditions. This case report is about a patient who presented with RPD, myoclonus, and other neurological symptoms and was found to have CJD on evaluation.

Case Report

A 65-year-old female was admitted to our hospital with complaints of altered sensorium for 10 days, impaired speech for 1 week with the inability to recognize his family members and an inability to perform daily activities of living. He also had involuntary jerky limb movements for past 1 week. There is no history of loss of consciousness, fever, seizures, sensory disturbance, limb weakness, vomiting, loose stools, or abdominal pain. On probing further, his family members confirmed that he had memory loss, visual hallucinations, and clumsiness of movements for the past 6 months. He became progressively forgetful and dependent on others in daily activities. His general health had been good, and he had no history of any surgery or blood transfusion, injection of growth hormone, or contact with farm animals. He had no peculiar dietary preferences. There was no family history of neurological diseases.

On examination, she was confused and irritable and occasionally obeyed simple commands. The cranial nerves and sensory system were normal. Examination of the motor system revealed a generalized hypertonia and exaggerated deep tendon reflexes. Myoclonic jerks were present in both upper and lower limbs during the examination. He had no signs of meningeal irritation.

Based on the history, examination, EEG, and MRI findings, we made a diagnosis of sporadic CJD. CSF 14-3-3 protein level could not be done due to nonavailability of the test in India. He was given intravenous immunoglobulin therapy for 5 days, supportive treatment, and anticonvulsants with physiotherapy. Patient gradually improved symptomatically and was discharged in a relatively stable condition with persistent memory impairment.

Discussion

CJD is a rare, fatal neurodegenerative disease with distinctive clinical and pathological features. Sporadic CJD usually appears at 50–70 years of age consisting 90% of all cases with CJD. The diagnosis of sporadic CJD is based on clinical symptoms along with laboratory tests including an EEG, CSF, and serum analysis for specific proteins such as S-100 protein, Tau protein, 14-3-3 protein, imaging, and pathology. CJD can be sporadic, infectious, or familial with 80%–90% of cases being sporadic. The WHO criteria for probable sporadic CJD are:

Exclusion of alternative diagnoses with routine investigations

RPD

At least two of the following four clinical features – myoclonus, visual disturbance or cerebellar dysfunction, pyramidal or extrapyramidal features, and akinetic mutism

The classical diagnostic presentation of CJD is a rapid cognitive decline with visual, cerebellar, pyramidal, or extrapyramidal signs, myoclonus, and abnormalities on EEG or diffusion-weighted MRI. The mean duration of illness is 4.5 months.[7]

There are three different stages of the disease during its clinical evolution:

Disease stage – Symptoms of progressive dementia, behavioral disorders, cognitive compromise, as well as clinical signs of pyramidal, extrapyramidal, and cerebellar compromise, as well as those of a lower motor neuron disease comprise the clinical picture. This has a mean duration of 4–5 months

Terminal stage – In this end-stage phase, the patient progresses to coma with myoclonic jerks, further evolving to abnormal decortication and decerebration postures, seizures, and dysautonomic symptoms. The duration varies according to the nursing care administered to the patient.[8]

The clinical features of CJD can sometimes be seen in mimics for CJD including Alzheimer's disease (AD) and less commonly dementia with Lewy bodies (DLBs). Neither AD nor DLB has the EEG or MRI changes seen in CJD.[9] EEG studies play an important role in the investigation and diagnosis of CJD when specific findings are found, thus allowing the clinician to progress in the investigation from a suspected case of CJD to a probable diagnosis status, which also has epidemiological repercussions.[10] Typical EEG findings of CJD are generalized complexes, either biphasic or triphasic, lasting for 100–300 ms, with a mean amplitude of 300 μV and an interval among repetitions of 0.5–1.5 s.[10],[11] May proposed, in 1968, a clinical staging for the disease, with a good correlation with EEG evolution.[12] In the prodromic phase, the clinical symptoms are somewhat vague such as headache, vertigo, confusion, and syncope. In this stage, the EEG shows a slowing of background activity, with both theta and delta waves with a generalized bilateral distribution, sometimes predominating over one hemisphere or the other. Furthermore, physiological sleep graph elements are lacking.[10],[11]

Myoclonic jerk may be seen in various conditions such as vascular, infectious, hypoxic, metabolic, degenerative, paraneoplastic, or autoimmune disease.[13] Cognitive decline and myoclonus can be present in subacute sclerosing panencephalitis and neurosyphilis, and some autoimmune disease such as Hashimoto's encephalitis. However, our patient's blood screening and CSF examination results were all negative, ruling out these disorders listed.[14] Patients with hypoxic encephalopathy and adult-onset lipid-storage diseases may mimic the symptoms, but our patient did not have the histories of these diseases. Mild myoclonus may occur in AD but with a slow clinical course.[15] However, our patient had a rapid clinical course.

Conclusion

CJD is a progressive neurological condition with fatal outcome. The early features of CJD vary and are nonspecific. Our patient's clinical presentation and EEG findings provided clues for diagnosis according to the WHO CJD criteria.[6] MRI of the brain in the early stages may give the clinician a hint to be aware of the possibility of CJD, although it is not included in diagnostic criteria. It is important for physicians to be cognizant of the clinical and investigative features of CJD to make a differential diagnosis. Early diagnosis is still a challenge in the early stages of CJD.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.